1. Field of the Invention
The present invention is directed to novel sulfonylhydrazines and their use as antineoplastic agents. The present invention also concerns methylating agents, especially N-methyl-N-sulfonylhydrazines, and their use as antineoplastic and trypanocidal agents.
2. Background Information
The synthesis and anticancer activity of a series of 1,2-bis(sulfonyl)-1-methylhydrazines was reported in K. Shyam, R. T. Hrubiec, R. Furubayashi, L. A. Cosby and A. C. Sartorelli, J. Med. Chem., 30, 2157-2161 (1987). Base-catalyzed decomposition to generate the putative methylating species RSO.sub.2 N.dbd.NMe was hypothesized to account for the observed biological activity.
Trypanosomes of the brucei group are flagellated protozoa which produce lethal infections in humans and domestic mammals throughout much of sub-Saharan Africa. (M. Katz, D. D. Depommier and R. W. Gwadz, Parasitic Diseases, Springer-Verlag, New York (1982); R. Allsopp, D. Hall and T. Jones, New Scientist, 7, 41-43 (1985); C. A. Hoare, Adv. Parasitol., 5, 47-91 (1967)). With the exception of alpha-difluoromethylornithine (DFMO), the trypanocidal drugs currently in use have been available for 25 to 80 years. Current treatment of early-stage infections consists of suramin for T. rhodesiense and pentamidine for T. gambiense (S. R. Meshnick, "The Chemotherapy of African Trypanosomiasis", In: Parasitic Diseases, J. M. Mansfield, ed., Marcel Dekker, Inc., New York (1984); F.I.C. Apted, Manson's Tropical Diseases, 18th edition, Bailliere Tindall, Eastbourne (1983), pp. 72-92; W. E. Gutteridge and G. H. Coombs, The Biochemistry of Parasitic Protozoa, Macmillan, London (1977), pp. 1-25).
These therapies require approximately six weeks of hospitalization due to drug toxicity. The only drug available for late-stage sleeping sickness is melarsoprol (S. R. Meshnick, supra). This drug has serious side-effects and up to 5% of patients die due to drug toxicity. Suramin, pentamidine and melarsoprol are all administered by intravenous injection. Recently, DFMO has been shown to be effective against early-stage sleeping sickness in man and animals. However, there are doubts as to its efficacy in late-stage disease unless it is used in combination with other less desirable agents such as bleomycin (P. P. McCann, G. J. Bacchi, A. B. Clarkson, Jr., J. R. Seed, H. C. Nathan, B. O. Amole, S. H. Hutner and A. Sjoerdsma, Medical Biol., 59, 434-440 (1983); A. B. Clarkson, Jr., C. J. Bacchi, G. H. Mellow, H. C. Nathan, P. P. McCann and A. Sjoerdsma, Proc. Natl. Acad. Sci. USA, 80, 5729-5733 (1983)). Therefore, better drugs are needed to treat trypanosomiasis.